Inappropriate angiogenesis is the cause or an aggravating factor in numerous disease states. For example, age related macular degeneration (ARMD) refers to a condition that steals away central vision but leaves peripheral (side) vision intact. This disease can be present in several forms and affects approximately 1 out of 5 individuals over the age of 65 and 1 out of 4 over the age of 75. That represents approximately 20 million Americans.
There are two forms of macular degeneration: dry macular degeneration and wet macular degeneration. The dry form, in which the cells of the macula slowly begin to break down, is diagnosed in 90 percent of macular degeneration cases. It may occur in one eye or both. The wet form, although it only accounts for 10 percent of the cases, results in 90 percent of the blindness. As the wet form worsens, patients begin to have abnormal blood vessels growing behind the macula. These vessels are very fragile and will leak fluid and blood (hence ‘wet’ macular degeneration), causing rapid damage to the macula. As of yet no specific pharmacological treatments are available.
The wet form of ARMD and other ocular diseases caused by the formation of new blood vessels (neovascularization) are among the leading causes of blindness. Thus there is a great need for the discovery of new drugs to treat such ocular diseases. One approach is to administer pharmaceutical anti-angiogenic agents to prevent the inappropriate neovascularization.
Novel anti-angiogenic compounds also have utility as anti-cancer agents. Malignancies are characterized by the growth and spread of tumors. One important factor in the progression of this disease is angiogenesis, a complex process in which capillary blood vessels grow in an ordered sequence of events. Once a tumor has started, every increase in tumor cell population must be preceded by an increase in new capillaries that converge on the tumor and supply the cells with oxygen and nutrients. Tumors may thus remain harmless and confined to their tissue of origin, as long as an accompanying angiogenic program is prevented from being activated. Since the angiogenesis-dependent step in tumor progression is shared by solid tumors of all etiologies, the ability to inhibit tumor-associated angiogenesis is a promising approach in combating cancer.
A substantial body of experimental evidence supports the hypothesis that tumor angiogenesis is fundamental for the growth and metastasis of solid tumors [Folkman, J. Natl. Cancer Inst., Vol. 82, pp. 4-6 (1989); N. Weidner, et al., Amer. J. Pathol., Vol. 143, pp. 401-409 (1993)]. Indeed, the majority of solid tumors are not even clinically detectable until after the occurrence of neovascularization, whose induction in solid tumors is mediated by one or more angiogenic factors.
Furthermore, angiogenesis is also important in a number of other pathological processes, including arthritis, psoriasis, diabetic retinopathy, chronic inflammation, scleroderma, hemangioma, retrolental fibroplasia and abnormal capillary proliferation in hemophiliac joints, prolonged menstruation and bleeding, and other disorders of the female reproductive system.
Accordingly, there is a need for compounds that have activity as anti-angiogenic agents and can be safely administered to patients to treat angiogenic-associated diseases. The present invention relates to a composition, comprising an anti-angiogenic compound, for use in treating angiogenic-associated diseases, as well as malignancies, including inhibition of primary tumor growth, tumor progression and metastasis. More particularly, the present invention is directed to thalidomide derivatives and their use as anti-angiogenic compositions.
Thalidomide was originally prescribed as a sedative, however its use was discontinued when it was found to be a potent teratogen, causing serious birth defects, especially affecting limb development. The dysmelia (limb defects) seen with thalidomide is proposed to be caused by an inhibition of blood vessel growth in the developing fetal limb bud. Although this affect is vasculogenic (affecting the formation of a capillary bed), studies have demonstrated that thalidomide is also anti-angiogenic (affecting the formation of new blood vessels from sprouts of pre-existing vessels). Thalidomide is relatively nontoxic, when taken by nonpregnant adults and is now in phase 2 clinical trials as a potential anti-cancer agent as well as a treatment for vascular eye diseases such as diabetic retinopathy, retinopathy of prematurity, and macular degeneration.
Thalidomide has been reported by Folkman, et. al. (PNAS, 91(9):4082-5, 1994) as having significant anti-angiogenic efficacy. The effects of thalidomide on corneal angiogenesis induced by vascular endothelial growth factor (VEGF), has been reported (Kruse et al, Graefes Archive for Clinical & Experimental Ophthalmology. 236(6):461-6, 1998). In Kruse et al, corneal neovascularization was induced in rabbits by an intrastromal pellet loaded with 500 or 750 ng VEGF. Animals receiving two daily feedings of 200 mg/kg of thalidomide, responded with statistically significant inhibition (P<0.0001) of corneal angiogenesis after the 5th day of treatment. This observation indicates that thalidomide has a significant anti-angiogenic effect against VEGF-induced ocular neovascular growth.
Thalidomide has also demonstrated inhibitory effects on angiogenesis in the basic fibroblast growth factor (bFGF) induced rabbit corneal micropocket assay and orally in mice models (Joussen et al. Graefes Archive for Clinical & Experimental Ophthalmology, 237(12):952-61, 1999 and Kenyon et al., Experimental Eye Research. 64(6):971-8, 1997). Thalidomide and a thalidomide analog (cc-1069) have been reported to inhibit the in vitro proliferation of endothelial cells (cells which make up the vascular system). The results of this study revealed a significant decrease in endothelial cell proliferation in cultures treated with thalidomide and/or cc-1069. Taken together, these data support a strong correlation between the anti-angiogenic potential and inhibition of endothelial cell proliferation for thalidomide.
Studies reveal that the S(−)-enantiomer of thalidomide has the strongest anti-angiogenic activity in both VEGF-induced and bFGF-induced corneal neovascularization. This enantioselective preference lends support to a possible receptor mediated mechanism. The present invention is directed to a novel series of thalidomide analogs and the use of such analogs as inhibitors of angiogenesis. More particularly, the thalidomide analogs of the present invention lack the piperidine-2,6-dione moiety of thalidomide.